Combinatorial expression of GPCR isoforms affects signalling and drug responses

Marti-Solano, M. et al. (2020) Combinatorial expression of GPCR isoforms affects signalling and drug responses. Nature, 587, pp. 650-656. (doi: 10.1038/s41586-020-2888-2) (PMID:33149304)

Abstract

G-protein-coupled receptors (GPCRs) are membrane proteins that modulate physiology across human tissues in response to extracellular signals. GPCR-mediated signalling can differ because of changes in the sequence1,2 or expression3 of the receptors, leading to signalling bias when comparing diverse physiological systems4. An underexplored source of such bias is the generation of functionally diverse GPCR isoforms with different patterns of expression across different tissues. Here we integrate data from human tissue-level transcriptomes, GPCR sequences and structures, proteomics, single-cell transcriptomics, population-wide genetic association studies and pharmacological experiments. We show how a single GPCR gene can diversify into several isoforms with distinct signalling properties, and how unique isoform combinations expressed in different tissues can generate distinct signalling states. Depending on their structural changes and expression patterns, some of the detected isoforms may influence cellular responses to drugs and represent new targets for developing drugs with improved tissue selectivity. Our findings highlight the need to move from a canonical to a context-specific view of GPCR signalling that considers how combinatorial expression of isoforms in a particular cell type, tissue or organism collectively influences receptor signalling and drug responses.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Quon, Dr Tezz and Milligan, Professor Graeme and Tobin, Andrew and MacKenzie, Dr Amanda
• Authors: Marti-Solano, M., Crilly, S. E., Malinverni, D., Munk, C., Harris, M., Pearce, A., Quon, T., Mackenzie, A. E., Wang, X., Peng, J., Tobin, A. B., Ladds, G., Milligan, G., Gloriam, D. E., Puthenveedu, M. A., and Babu, M. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Nature
• Publisher: Nature Research
• ISSN: 0028-0836
• ISSN (Online): 1476-4687
• Published Online: 04 November 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Nature 587:650-656
• Publisher Policy: Reproduced in accordance with the publisher copyright policy

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
173305		Defining the functional roles of the enigmatic G protein coupled receptor GPR35	Graeme Milligan	Biotechnology and Biological Sciences Research Council (BBSRC)	BB/P000649/1	MCSB - Molecular Pharmacology
173689		Defining the functional role of the enigmatic G protein coupled receptor GPR35 - Leicester application - PART B	Andrew Tobin	Biotechnology and Biological Sciences Research Council (BBSRC)	BB/P00069X/1	MCSB - Administration